The substituted catechol compounds have a great commercial importance in the synthesis of pharmaceutical compounds. 2,3-dihydroxy benzonitrile of Formula I, a substituted catechol compound is an important starting material for the preparation of a number of valuable heterocyclic compounds which are medicinally important. 2,3-dihydroxy benzonitrile is the key starting material for Desferrithiocin and its analogues. Desferrithiocin (DFT) is an orally effective iron chelator, with a similar high affinity and selectivity for iron to desferrioxamine (DFO), which has been shown clinically to possess antineoplastic activity. Therefore the commercial production for 2,3-dihydroxy benzonitrile is utmost important.

Several conventional processes for the preparation of 2,3-dihydroxy benzonitrile are available in the literature. Various other procedures in the literature cites the preparation of 2,3-dihydroxy benzonitrile from different starting materials (substituted catechol compounds). A practically more suitable process for the preparation of 2,3-dihydroxy benzonitrile is from the corresponding precursor 2,3-dialkoxy benzoic acid. A person skilled in the art expects the process to proceed from acid halide, amide, nitrile and dealkylation, wherein the dealkylation step is mandatory to obtain the title compound, Chemical and Pharmaceutical bulletin vol. 58, 11, 2010, 1552-1553 discloses the process for preparation of 2,3-dihydroxy benzonitrile from 2,3-dihydroxy benzaldehyde in the presence of formic acid, hydroxylamine hydrochloride and sodium formate.
European Journal of Organic Chemistry 11, 2006, 2513-2516 discloses the process for preparation of 2,3-dihydroxy benzonitrile from 1,3-benzodioxole-4-carbaldehyde. Oxidative conversion of aldehydes to nitriles and deprotection of hydroxy groups done in the presence of 2.2 eq of sodium hexamethyldisilazane in tetrahydrofuran and in highly polar solvent 1,3-Dimethyl-2-imidazolidinone at 185° C. in a sealed tube.
Several reviews have been described for deprotection of phenolic ethers. For example, phenolic methyl ethers have deprotected to remove the methyl moiety using hydrogen halide such as hydrogen chloride or hydrogen bromide under highly acidic conditions; highly dark colored products formed in these reactions. In addition the phenolic compounds react further with the halogen compounds used thus setting a major drawback on this route.
Use of Lewis acids such as aluminum chloride or aluminum bromide in dealkylation is well known in the art. U.S. Pat. No. 7,253,324 discloses a process of poly O-dealkylation of alkoxy aromatic compounds using a aluminum chloride-N,N-dimethylaniline complex. However the patent restricts towards manufacture of polyphenols such as Resveratrol, Oxyresveratrol and Gnetol.
A conventional process for producing 2,3-dihydroxy benzonitrile from 2,3-dimethoxy benzonitrile is disclosed in Journal of Medicinal Chemistry, 2005, Vol. 48, No. 3, 821-831. The disclosed process appears to be the closest prior art involving demethylation in the presence of boron tribromide in dichloromethane.
Boron tribromide is highly moisture sensitive, colorless fuming liquid and decomposes in air with evolution of HBr. It is stored under a dry inert atmosphere and transferred by syringe or through a Teflon tube for the reactions. It reacts violently with protic solvents such as water and alcohols. However the aforementioned process for preparing 2,3-dihydroxy benzonitrile are less than fully satisfactory in view of hazardous reagents, difficult to handle, expensive, lower temperatures, long reaction times, tedious work up procedures, not liable for scale up process and low reaction yields, thereby limiting their use in commercial scale production.
Despite all prior advances, available methods for synthesizing 2,3-dihydroxy benzonitrile from 2,3-dialkoxy benzoic acid which proceed through known intermediates such as the corresponding acid 2,3-dialkoxy benzoyl chloride, 2,3-dialkoxy benzamide, 2,3-dialkoxy benzonitrile remain labor intensive, time consuming and environmentally unfavorable. The isolated intermediates are however available in the literature, wherein the isolation of the intermediated are time consuming and practically not suitable for manufacturing scales. Thus, there remains a need for a simple, cost effective, industrially feasible and scalable process for the synthesis of 2,3-dihydroxy benzonitrile that would avoid the aforementioned difficulties.
The present inventors thus found an alternate approach for preparing 2,3-dihydroxy benzonitrile involving a one-pot synthesis from 2,3-dialkoxy benzoic acid without isolating any intermediates and also involving the use of aluminum salt-amine complex for the dealkylation process.